Project Summary In addition to genetic and epigenetic changes, c ancer progression is accompanied by widespread metabolic alterations to meet the demands of abnormally proliferating cells. In pancreatic cancer, the metabolic signatures of malignant cells are not passive responses but a direct result from mutant KRAS-mediated reprogramming of glucose and glutamine metabolism to support anabolic growth. As those metabolic pathways are dispensable in normal cells, yet essential in cancer, they may represent an Achilles' heel for cancer therapeutics. At the molecular level, KRAS-driven metabolic rewiring depends on c-MYC, a master regulator of cancer metabolism which is frequently amplified and upregulated during neoplastic progression. By using a systems biology approach we discovered that KDM5A (also known as RBP2 and JARID1A), a Jumonji C domain histone H3K4 demethylase, is frequently amplified and markedly overexpressed in human pancreatic cancer. Gain and loss-of- function experiments coupled to genome-wide expression and chromatin immunoprecipitation studies revealed that KDM5A drives tumorigenicity through metabolic reprogramming by co-operating with c- MYC. KDM5A binds and regulates the expression of metabolic enzymes, as well as mediators of protein synthesis and mitochondrial function, suggesting the existence of an epigenetic switch that regulates metabolic reprogramming in cancer. To this end, we generated new genetically engineered mouse models to either knock out or conditionally overexpress wild type and a catalytically inactive mutant of KDM5A in pancreas. Compound mutants of those mice that also have pancreas-specific activation of KrasG12D will be used to (a) delineate the role of this epigenetic regulator in pancreatic cancer initiation and maintenance, and (b) comprehensively map the epigenetic changes that rewire the pancreatic cancer metabolome. Given the reversibility of histone modifications, small molecule inhibitors of KDM5A may provide novel therapeutic opportunities.